Unacylated Ghrelin to Improve FuncTioning in PAD: the GIFT Trial Our work and that of others shows that patients with lower extremity peripheral artery disease (PAD) have greater functional impairment, faster functional decline, and higher rates of mobility loss compared to people without PAD. In patients with PAD, ischemia results in calf muscle injury that includes myofiber loss and calf muscle mitochondrial dysfunction. Therapies to regenerate calf skeletal muscle cells, improve mitochondrial function, and increase calf muscle capillary density may improve functioning and prevent mobility loss in people with PAD. Yet few effective therapies currently exist for patients with PAD. This pilot study will investigate the therapeutic potential of unacylated ghrelin to promote capillary growth, increase calf muscle perfusion, and reverse PAD-related skeletal muscle abnormalities, thereby improving PAD-related functional impairment. Ghrelin is a peptide and hormone that circulates in acylated and unacylated forms. Unacylated ghrelin promotes skeletal muscle cell regeneration, improves mitochondrial function, and increases muscle capillary density. Unlike acylated ghrelin, unacylated ghrelin does not increase appetite, or cause insulin resistance. The proposed GIFT Trial will provide preliminary data to test our hypothesis that unacylated ghrelin improves walking performance and prevents mobility loss in older patients with PAD. We further hypothesize that the favorable effect of unacylated ghrelin will be mediated by increased myofiber regeneration, increased muscle capillary density, and improved muscle mitochondria function. If our preliminary data support our hypotheses, results will be used to design a large randomized trial of unacylated ghrelin therapy, in subsequent study, to improve functioning and prevent mobility loss in older people with PAD. We will conduct a pilot randomized trial in 30 participants age 60 and older with PAD, to gather preliminary evidence about whether daily subcutaneously administered unacylated improves the six-minute walk distance (primary outcome), maximal treadmill walking distance (secondary outcome), and calf muscle perfusion (secondary outcome), compared to placebo. We will also perform calf muscle biopsies at baseline and follow up to determine whether unacylated ghrelin increases Type 1 skeletal muscle myofibers, satellite cell number, capillary density, and succinate dehydrogenase (SDH) mitochondrial activity in calf skeletal muscle, compared to placebo. If our hypotheses are correct, results will be used to design a large, definitive randomized trial of unacylated ghrelin to improve lower extremity functioning and prevent mobility loss in the large and growing number of older people who are disabled by PAD.